Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a hydrazone moiety as potent PLK1 inhibitors

Zhiwei Li; Le Xu; Liangyu Zhu; Yanfang Zhao; Tao Hu; Bixi Yin; Yajing Liu; Yunlei Hou

doi:10.1016/j.bmcl.2020.127329

Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a hydrazone moiety as potent PLK1 inhibitors

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127329. doi: 10.1016/j.bmcl.2020.127329. Epub 2020 Jun 8.

Authors

Zhiwei Li¹, Le Xu¹, Liangyu Zhu¹, Yanfang Zhao¹, Tao Hu², Bixi Yin², Yajing Liu³, Yunlei Hou⁴

Affiliations

¹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
² Yangtze River Pharmaceutical Group Pharmaceutical Co., Ltd, 1 South Yangtze River Road Taizhou, Jiangsu 225321, China.
³ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: lyjpharm@126.com.
⁴ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Yangtze River Pharmaceutical Group Pharmaceutical Co., Ltd, 1 South Yangtze River Road Taizhou, Jiangsu 225321, China. Electronic address: houyunlei901202@163.com.

PMID: 32631534
DOI: 10.1016/j.bmcl.2020.127329

Abstract

A series of novel pteridinone derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most of the synthesized compounds demonstrated moderate to excellent activity against A549, HCT116 and PC-3 cancer cell lines. In particular, compound L₁₉ exhibited the most potent antiproliferative effects on three cell lines with IC₅₀ values of 3.23 μM, 4.36 μM and 8.20 μM, respectively. In kinase assays, the compound L₁₉ also showed potent inhibition activity toward PLK1 with % inhibition values of 75.1. Further mechanism studies revealed that compound L₁₉ significantly inhibited proliferation of HCT-116 cell lines, induced a great decrease in mitochondrial membrane potential resulting in apoptosis of cancer cells, inhibited the migration of tumor cells, and arrested G1 phase of HCT116 cells.

Keywords: Anti-cancer; PLK1; Pteridinone derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Hydrazones / chemistry
Hydrazones / pharmacology*
Molecular Structure
Polo-Like Kinase 1
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pteridines / chemical synthesis
Pteridines / chemistry
Pteridines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cell Cycle Proteins
Hydrazones
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pteridines
Protein Serine-Threonine Kinases